Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview.

Cytokines are immune modulators which can enhance the immune response and have been proven to be an effective class of immunotherapy. Nevertheless, the clinical use of cytokines in cancer treatment has faced several challenges associated with poor pharmacokinetic properties and the occurrence of adverse effects. Immunocytokines (ICKs) have emerged as a promising approach to overcome the pharmacological limitations observed with cytokines. ICKs are fusion proteins designed to deliver cytokines in the tumor microenvironment by taking advantage of the stability and specificity of immunoglobulin-based scaffolds. Several technological approaches have been developed. This review focuses on ICKs designed with the most impactful cytokines in the cancer field: IL-2, TNFα, IL-10, IL-12, IL-15, IL-21, IFNγ, GM-CSF, and IFNα. An overview of the pharmacological effects of the naked cytokines and ICKs tested for cancer therapy is detailed. A particular emphasis is given on the immunomodulatory effects of ICKs associated with their technological design. In conclusion, this review highlights active ways of development of ICKs. Their already promising results observed in clinical trials are likely to be improved with the advances in targeting technologies such as cytokine/linker engineering and the design of multispecific antibodies with tumor targeting and immunostimulatory functional properties.

Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer.

Although immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, we found that the intratumoral expression of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which regenerates inactive glucocorticoids into active glucocorticoids, was associated with poor clinical outcome and correlated with immunosuppressive gene signatures in patients with renal cell carcinoma (RCC). HSD11B1 was mainly expressed in tumor-infiltrating immune myeloid cells as seen by immunohistochemistry in RCC patient samples. Using peripheral blood mononuclear cells from healthy donors or immune cells isolated from the tumor of RCC patients, we showed that the pharmacological inhibition of HSD11B1 improved the response to the immune checkpoint inhibitor anti-PD-1. In a subcutaneous mouse model of renal cancer, the combination of an HSD11B1 inhibitor with anti-PD-1 treatment increased the proportion of tumor-infiltrating dendritic cells. In an intrarenal mouse tumor model, HSD11B1 inhibition increased the survival of mice treated with anti-PD-1. In addition, inhibition of HSD11B1 sensitized renal tumors in mice to immunotherapy with resiquimod, a Toll-like receptor 7 agonist. Mechanistically, we demonstrated that HSD11B1 inhibition combined with resiquimod increased T cell-mediated cytotoxicity to tumor cells by stimulating the antigen-presenting capacity of dendritic cells. In conclusion, these results support the use of HSD11B1 inhibitors to improve the outcome of immunotherapy in renal cancer and highlight the role of the endogenous glucocorticoid metabolism in the efficacy of immunotherapy.